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      Genome-Wide Association Study of Serum Selenium Concentrations

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          Abstract

          Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women’s Health Initiative (WHI). We tested association between 2,474,333 single nucleotide polymorphisms (SNPs) and serum selenium concentrations using linear regression models. In the first stage (PLCO) 41 SNPs clustered in 15 regions had p < 1 × 10 −5. None of these 41 SNPs reached the significant threshold ( p = 0.05/15 regions = 0.003) in the second stage (WHI). Three SNPs had p < 0.05 in the second stage (rs1395479 and rs1506807 in 4q34.3/ AGA- NEIL3; and rs891684 in 17q24.3/ SLC39A11) and had p between 2.62 × 10 −7 and 4.04 × 10 −7 in the combined analysis (PLCO + WHI). Additional studies are needed to replicate these findings. Identification of genetic variation that impacts selenium concentrations may contribute to a better understanding of which genes regulate circulating selenium concentrations.

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          Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group.

          SR Johnson, M Henderson, C Furberg … (1998)
          The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the components--dietary modification (DM) or hormone replacement therapy (HRT)--of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.
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            Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

            Philip C Prorok, Gerald Andriole, Robert Bresalier … (2000)
            The objectives of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial are to determine in screenees ages 55-74 at entry whether screening with flexible sigmoidoscopy (60-cm sigmoidoscope) can reduce mortality from colorectal cancer, whether screening with chest X-ray can reduce mortality from lung cancer, whether screening men with digital rectal examination (DRE) plus serum prostate-specific antigen (PSA) can reduce mortality from prostate cancer, and whether screening women with CA125 and transvaginal ultrasound (TVU) can reduce mortality from ovarian cancer. Secondary objectives are to assess screening variables other than mortality for each of the interventions including sensitivity, specificity, and positive predictive value; to assess incidence, stage, and survival of cancer cases; and to investigate biologic and/or prognostic characterizations of tumor tissue and biochemical products as intermediate endpoints. The design is a multicenter, two-armed, randomized trial with 37,000 females and 37,000 males in each of the two arms. In the intervention arm, the PSA and CA125 tests are performed at entry, then annually for 5 years. The DRE, TVU, and chest X-ray exams are performed at entry and then annually for 3 years. Sigmoidoscopy is performed at entry and then at the 5-year point. Participants in the control arm follow their usual medical care practices. Participants will be followed for at least 13 years from randomization to ascertain all cancers of the prostate, lung, colorectum, and ovary, as well as deaths from all causes. A pilot phase was undertaken to assess the randomization, screening, and data collection procedures of the trial and to estimate design parameters such as compliance and contamination levels. This paper describes eligibility, consent, and other design features of the trial, randomization and screening procedures, and an outline of the follow-up procedures. Sample-size calculations are reported, and a data analysis plan is presented.
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              Food-chain selenium and human health: emphasis on intake.

              Margaret P Rayman (2008)
              Following the publication of the landmark trial of Clark et al. in 1996 that appeared to show that Se could reduce the risk of cancer, awareness of the importance of Se to human health has markedly increased. As a result, there is now much more aggressive marketing of Se supplements and functional foods, even in situations where additional consumption of Se is inappropriate. The present review addresses how Se gets into the food chain, the wide variability in Se content of foods and the very different levels of intake between countries and regions. Though it is clear that there are adverse consequences for health of both deficient and excessive intake, health effects at intermediate levels of intake are less certain. Thus it is difficult to define optimal intake which depends on a large number of factors, such as which functions of Se are most relevant to a particular disease state, which species of Se is most prominent in the Se source, which health condition is being considered, the adequacy or otherwise of intake of other nutrients, the presence of additional stressors, and lastly whether the ability to make selenoproteins may be compromised. These complexities need to be understood, particularly by policy makers, in order to make informed judgments. Potential solutions for increasing Se intake, where required, include agronomic biofortification and genetic biofortification or, for individuals, increased intake of naturally Se-rich foods, functional foods or supplements. The difficulties of balancing the risks and benefits in relation to Se intake are highlighted.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nutrients
                Journal ID (iso-abbrev): Nutrients
                Journal ID (publisher-id): nutrients
                Title: Nutrients
                Publisher: MDPI
                ISSN (Electronic): 2072-6643
                Publication date (Electronic): 21 May 2013
                Publication date Collection: May 2013
                Volume: 5
                Issue: 5
                Pages: 1706-1718
                Affiliations
                [1 ]Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; E-Mails: jgong@ 123456fhcrc.org (J.G.); lih@ 123456fhcrc.org (L.H.); tharriso@ 123456fhcrc.org (T.H.); xsong2@ 123456fhcrc.org (X.S.)
                [2 ]Department of Biostatistics, University of Washington, Seattle, WA 98195, USA
                [3 ]Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA; E-Mail: IKing@ 123456salud.unm.edu
                [4 ]Department of Pharmacy, University of Copenhagen, Copenhagen, DK-2100, Denmark; E-Mail: stefan.sturup@ 123456sund.ku.dk
                [5 ]Translational Genomics Research Institute, Phoenix, AZ 85004, USA; E-Mail: dduggan@ 123456tgen.org
                [6 ]Stephens and Associates, Carrollton, TX 75006, USA; E-Mail: yliu@ 123456stephens-associates.com
                [7 ]Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD 20892, USA; E-Mail: huttercm@ 123456mail.nih.gov
                [8 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA; E-Mail: hanocks@ 123456mail.nih.gov
                [9 ]Center for Primary Care and Prevention, Memorial Hospital of Rhode Island, Pawtucket, RI 02860, USA; E-Mail: Charles_Eaton@ 123456mhri.org
                [10 ]Department of Health Behavior, Roswell Park Cancer Institute, Buffalo, NY 14263, USA; E-Mail: James.Marshall@ 123456RoswellPark.org
                [11 ]Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA 98195, USA
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: upeters@ 123456fhcrc.org ; Tel.: +1-206-667-2450; Fax: +1-206-667-7850.
                Article
                Publisher ID: nutrients-05-01706
                DOI: 10.3390/nu5051706
                PMC ID: 3708345
                PubMed ID: 23698163
                SO-VID: 29efc2e8-420e-4076-80b7-19f3fd32b95a
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 02 February 2013
                Date revision received : 02 May 2013
                Date accepted : 09 May 2013
                Categories
                Subject: Article

                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: selenium,serum,selenoprotein,genome-wide association study,aga,neil3,slc39a11
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: selenium, serum, selenoprotein, genome-wide association study, aga, neil3, slc39a11

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